Biological molecules targeting proteins that undergo internalization offer a number of advantages. When labeled with either a diagnostic or therapeutic agent they carry the label/prosthetic group inside the cell and once inside the conjugate can enhance contrast for diagnostic agents and/or deliver its therapeutic effects. The process of internalization can also enhance cytotoxic potency as in the case of radioimmunotherapy when radioisotopes with short effective ranges are used.
Labeled biological molecules or conjugates are typically prepared by using a linker to append the label to the biological molecule so that minimal damage is done to the compound and affinity is maintained for the target. Biological molecules labeled in this fashion and then internalized can undergo rapid intracellular degradation. This is an enzyme-catalyzed event that breaks the conjugate down into small peptides and/or individual amino acids. As a result the label is liberated from the conjugate and often egresses from the target cells. In the case of diagnostic agents this significantly lowers target to non-target ratios and with respect to therapeutic agents this can lead to significant undesirable off target toxicity.
Residualizing linkers are designed to retain the label intracellularly after lysosomal degradation of the internalized biological conjugate. This results in overall greater retention in the cells leading to better target-to-non-target ratios and therapeutic effects.